WO2022207979A2 - Nouveaux composés hétérocycliques et leur utilisation - Google Patents

Nouveaux composés hétérocycliques et leur utilisation Download PDF

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WO2022207979A2
WO2022207979A2 PCT/FI2022/050205 FI2022050205W WO2022207979A2 WO 2022207979 A2 WO2022207979 A2 WO 2022207979A2 FI 2022050205 W FI2022050205 W FI 2022050205W WO 2022207979 A2 WO2022207979 A2 WO 2022207979A2
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group
compound
methyl
per
pharmaceutically acceptable
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PCT/FI2022/050205
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English (en)
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WO2022207979A3 (fr
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Ville Takio
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Equinorm Ltd
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Priority to IL307377A priority Critical patent/IL307377A/en
Priority to EP22715649.4A priority patent/EP4313985A2/fr
Priority to CN202280039184.5A priority patent/CN117412975A/zh
Priority to BR112023020273A priority patent/BR112023020273A2/pt
Priority to AU2022249834A priority patent/AU2022249834A1/en
Priority to KR1020237037343A priority patent/KR20240004396A/ko
Priority to JP2023561049A priority patent/JP2024511886A/ja
Priority to CA3215457A priority patent/CA3215457A1/fr
Publication of WO2022207979A2 publication Critical patent/WO2022207979A2/fr
Publication of WO2022207979A3 publication Critical patent/WO2022207979A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds derived from substituted 1,2,3,6-tetrahydropyridines and 2,3-dihydropyridines and pharmaceutical compositions comprising said compounds. More particularly, the present invention relates to novel compounds derived from 1,2- or 2,3- disubstituted 1,2,3,4-tetrahydroisoquinolines and -2,3,4,9-tetrahydro-l//- pyrido [3, 4-h] indoles, and l-methyl-4,9-dihydro-3//-, and l-methyl-2, 3,4,9- tetrahydro-l//-pyrido[3,4-b]indoles.
  • the invention also relates to said compounds for use in the treatment or prevention of drug addiction and CNS related diseases, in addition to methods for the preparation of said derivatives.
  • tetrahydroharman l-methyl-l,2,3,4-tetrahydro-p-carboline
  • Reserpine another indole alkaloid with a tetrahydropyridine structure, is used as a drug for treating hypertension and has also shown to exhibit effects in relieving psychotic symptoms.
  • tetrahydropyridine derivatives with a fused indole ring are tryptoline (tetrahydro-p-carboline, 1,2, 3,4- tetrahydro-9//-pyrido [3, 4-b] indole), pinoline (5-methoxytryptoline), tetrahydroharmine ((lR)-7-methoxy-l-methyl-2,3,4,9-tetrahydro-l//-pyrido[3,4- bjindole), harmaline (7-methoxy-l-methyl-4,9-dihydro-3//-pyrido[3,4-b]indole), and tetrahydroharmine ((lf?)-7-methoxy-l-methyl-2,3,4,9-tetrahydro-l//- pyrido [3, 4-b] indole) that show various effects including psychoactivity, monoamine oxidase inhibition activity, serotonin re
  • gevotroline (8-fluoro-2-(3-(pyridin-3- yl)propyl)-2,3,4,5-tetrahydro-l//-pyrido[4,3-b]indole) is an atypical antipsychotic that was developed for the treatment of schizophrenia, however, the compound never research the market.
  • latrepirdine (dimebolin, 2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro- l//-pyrido[4,3-b]indole), is an antihistamine drug that failed in phase III clinical trials for both the treatment of Alzheimer’s and Huntington’s disease.
  • Endogenous isoquinolines show a various of effects including sedative, psychotropic and analgesic properties, morphine and codeine being well known examples of isoquinoline alkaloids.
  • Endogenous isoquinolines are formed by condensation of biogenic amines - such as phenethylamine - and simple aldehydes, such as formaldehyde or acetaldehyde. They are known to modulate neurotransmission, central metabolism and motor activity.
  • TIQ tetrahydroisoquinoline
  • SAL Parkinson’s disease
  • R R-lMeTIQ (1-methyl-l, 2,3,4- tetrahydroisoquinoline) was shown to possess an antiparkinsonian activity.
  • 1-MeTIQ was the only known neuroprotective/PD preventing TIQ derivative.
  • Katsuhiro OKUDA et al. Biological and Pharmaceutical Bulletin 29 (2006) pp. 1401-1403
  • 5-/6-/7-monohydroxylated IMeTlQ derivatives are neuroprotective and PD preventing indeed, even more so than the parent compound.
  • SAL is formed enzymatically as well as non-enzymatically as a condensation product of acetaldehyde - the primary metabolite of ethanol - with dopamine in the brain of mammals.
  • SAL affects the uptake of catecholamines into nerve terminals, the release of stored catecholamines and the activity of monoamine oxidase (MAO), catechol-O-methyl transferase (COMT) and tyrosine hydroxylase.
  • MAO monoamine oxidase
  • COMP catechol-O-methyl transferase
  • tyrosine hydroxylase tyrosine hydroxylase
  • SAL has been postulated to mediate some of the addictive properties of alcohol.
  • a number of studies have shown that primates self-administer SAL even in nanomolar concentrations when intracranially injected to certain brain region. Also acetaldehyde is self-administered when injected intracranially although much higher concentrations are needed.
  • Studies have confirmed that SAL is released during suckling on lactating sheep. It is clear that SAL mediates reinforcing effects on a number of primate species.
  • Studies have shown that controlled amounts of ethanol intake have only miniscule effect on brain SAL levels.
  • TlQs penetrate to the brain in pharmacologically relevant amounts and induce a variety of effects. Most of the T1Q and IMeTIQ exit the brain (90.4% and 95.3%) and is excreted in urine (76% and 72%) unchanged.
  • the hydroxylated (C4 of the isoquinoline backbone) derivatives of T1Q and IMeTIQ were the most abundant metabolites in the urine (2.7% and 8.7%).
  • EP 2 090 576 A1 discloses certain 5,8- and 6,7-difluoro substituted isoquinolines as intermediates in the preparation of pyrazolo[l,5-a]pyridines for use as metabotropic glutamate receptor modulators.
  • WO 2002028865 A2 discloses certain specifically substituted 2, 3,4,9- tetrahydro-l//-pyrido[3,4-b]indoles as selective inhibitors of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase.
  • EP 3 459950 A1 discloses certain b-carboline, dihydro-p-carboline and tetrahydro-p-carboline alkaloid compounds with anti-plant virus activity and are disclosed to also have fungicidal and insecticidal activities.
  • W0 2012/020170 discloses 6,7-disubstituted- 1-methyl- 1,2, 3,4- tetrahydro- and -3,4-dihydroisoquinolines for use in the treatment of drug addiction and CNS related diseases.
  • An object of the present invention is to provide compounds useful in treating disorders and diseases associated with drug addiction and CNS related diseases.
  • One of the problems associated with the known compounds is the disposition, in particular the metabolic stability, of the compounds. It is therefore yet a further object of the present invention to provide compounds with improved metabolic stability.
  • the invention is based on the realization that the compounds of the invention bind to and/or affect the activity of proteins that are associated with drug addiction and CNS related diseases.
  • the present invention provides novel compounds of formula (1) wherein the dotted line represents an optional bond;
  • R 1 and R 2 together with the carbon atoms they are attached to, form a group selected from a 1H-indole group and a benzene group, and said 1H-indole group and benzene group being optionally substituted with one to four substituent(s) each independently selected from the group consisting of R 3 , R 4 , R 5 , and R 6 , wherein each R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of halogen, OH, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, C1-3- (per)haloalkoxy;
  • R a and R b together with the carbon atom and nitrogen atom they are attached to, form a group selected from a 5- and 6-membered cyclic amide, and
  • R c is H
  • R a is Me
  • R b and R c together with the nitrogen atom and carbon atom they are attached to, form a group selected from a 5- and 6-membered cyclic amide; or R a is Me,
  • R b is H, or R b is absent when the dotted line represents a bond
  • R c is H, provided that R 1 and R 2 , together with the carbon atoms they are attached to, form said optionally substituted 1H-indole group;
  • R 7 is selected from the group consisting of halogen, OH, oxo, SH, NOR 8 , C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy, CN, C(0)N(R 8 )2, and N(R 8 )2, or
  • R 7 may also be C 1-4 -alkyl with the provisio that said 1H-indole group or benzene group is substituted with one to four substituent(s) each independently selected from the group consisting of halogen, OH, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, C 1 - 3 -(per)haloalkoxy, or
  • R 7 may also be H provided that when R a and R b , together with the carbon atom and nitrogen atom they are attached to, form a group selected from a 5- and 6-membered cyclic amide, R c is H, then R 4 and R 5 is each independently selected from the group consisting of halogen, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, and C 1-3 -(per)haloalkoxy, or when R a is Me, R b and R c , together with the carbon atom and nitrogen atom they are attached to, form a 6-membered cyclic amide, then R 1 and R 2 , together with the carbon atoms they are attached to, form said optionally substituted 1H-indole group, or when R a is Me, R b and R c , together with the carbon atom and nitrogen atom they are attached to, form a 5-membered cyclic amide, and R 1 and R 2 , together with the carbon
  • the invention also relates to pharmaceutical compositions comprising an effective amount of one or more compound(s) of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipient(s).
  • the invention relates to a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, for use as a medicament.
  • invention relates to a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, for use in treatment or prevention of CNS related diseases or conditions.
  • the invention also relates to a compounds of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, depression, anxiety, hyperactivity, narcolepsy, drug addiction, alcoholism, anorexia, bulimia, and mitochondrial disease.
  • Compounds of the invention are derivatives of 1,2, 3, 6- tetrahydropyridine and 2, 3 -dihydropyridine that are fused at C4 and C5 to either an optionally substituted l/f-indole ring or an optionally substituted benzene ring that, together with the specific substitution pattern of the 1, 2,3,6- tetrahydropyridine and 2,3-dihydropyridine rings, provide the inventive properties of the compounds of the present invention. Also, the substitution of said 1/i-indole and benzene ring further enhance the metabolic and/or inhibitory properties of the compounds of the present invention.
  • halogen as used herein and hereafter by itself or as part of other groups refers to the Group Vila elements and includes F, Cl, Br and I groups, preferably F.
  • alkyl as used herein and hereafter is an aliphatic linear, branched or cyclic, especially linear or branched, hydrocarbon group having the indicated number of carbon atoms, for example C 1-6 -alkyl has 1 to 6 carbon atoms in the alkyl moiety and thus, for example, C 1-4 -alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and C 1-6 -alkyl additionally includes branched and straight chain pentyl and hexyl.
  • the alkyl is methyl or ethyl.
  • C 1-4 -alkenyl as used herein and hereafter is an unsaturated linear or branched hydrocarbon group having at least one olefinic double bond between any two carbon atoms and having suitably 1 to 4, preferably 1 to 3, carbon atoms in the alkenyl moiety, such as ethenyl, 1-propenyl, 2-propenyl, 3-propenyl, and butenyl.
  • alkenyls groups include, but are not limited to, linear alkenyl groups having a terminal double bond such as vinyl and allyl groups.
  • C 1-4 -alkynyl as used herein and hereafter is an unsaturated linear or branched hydrocarbon group having at least one olefinic triple bond between any two carbon atoms and having suitably 1 to 4, preferably 1 to 2, carbon atoms in the alkenyl moiety, such as ethynyl, propynyl, and butynyl.
  • C 1-3 -(per)haloalkyl refers to any of the above alkyl groups where one or more hydrogen atoms are replaced by halogen (s): in particular 1, Br, F or Cl.
  • haloalkyl groups include without limitation chloromethyl, fluoromethyl and -CH2CF3.
  • perhaloalkyl is understood to refer to an alkyl group, in which all the hydrogen atoms are replaced by halogen atoms. Preferred examples include trifluoromethyl (-CF 3 ) and trichloromethyl (-CCI 3 ).
  • C 1-3 -alkoxy refers to a -0-( C 1-3 - alkyl) group where the " C 1-3 -alkyl” has the above-defined meaning.
  • preferred alkoxy groups include, but are not limited to, methoxy, ethoxy, and iso- propyloxy.
  • C 1-3 -(per)haloalkoxy refers to a -0-(C 1-3 -(per)haloalkyl) group where the C 1-3 -(per)haloalkyl has the above- defined meaning.
  • preferred alkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2 -trichloromethoxy, and 1,1, 1,3,3, 3-hexafluoro- isopropoxy.
  • 5- and 6-membered cyclic amide refers to a 5- and 6-membered lactam that may or may not comprise other heteroatoms, such as N, 0, and S, and substituents, such as methyl, hydroxy, amine, thiol and methoxy.
  • Examples of preferred 5- and 6-membered cyclic amide groups include, but are not limited to, 2-pyrrolidone, 2-piperidinone, imidazolidin- 2-one, oxazolidin-2-one, oxazolidin-4-one, imidazolidin-4-one, tetrahydropyrimidin-2(l//)-one, l,3-oxazinan-2-one, piperazin-2-one, thiomorpholin-3-one, 4-methylpiperidin-2-one, and 5-hydroxypiperidin-2-one.
  • NOR 8 refers to a functional group, which, together with the carbon atom to which the nitrogen of NOR 8 is attached to and a carbon-nitrogen double bond between said carbon atom and said nitrogen atom, forms an oxime functional group of a ketoxime compound disclosed herein and said oxime functional group may or may not be substituted at the oxygen atom of the oxime functional group, wherein R 8 is as defined herein and hereafter. Therefore, when R 7 is NOR 8 , it is to be understood that the carbon atom to which the nitrogen atom of NOR 8 is attached to, does not contain one or more hydrogen atoms. Said NOR 8 may be synthesized e.g.
  • NOR 8 groups include, but are not limited to, hydroxyimino, methoxyimino, (trifluoromethoxy)imino, and (2,2,2,- trifluoro ethoxy) imino, and (£)- and (Z)-isomers thereof.
  • 3- to 6-membered aliphatic or aromatic heterocyclic ring comprising 1 to 3 heteroatoms each independently selected from N, 0, and S refers to a monocyclic ring which is saturated, partially unsaturated, unsaturated or aromatic with 3 to 6 ring atoms that may or may not comprise one or more double bond between the ring atoms and said monocyclic ring comprises 1 to 3 heteroatom(s) each independently selected from the group consisting of N, S, and 0, while the remaining ring atoms are carbon atoms. It may be substituted with one to four substituent(s) at any suitable ring atom, including N.
  • Preferred substituents groups include, but are not limited to halogen, in particular fluoro, CN, methoxy, hydroxy, amino, and methyl.
  • heterocyclic rings include, but are not limited to, aziridinyl, azetidinyl, 1,3- diazetidinyl, pyrazolidinyl, imidazolidinyl, imidazolyl, piperidinyl, dihydrothiazolyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, dioxide of thiomorpholinyl, and methoxymethylpyrrolidinyl.
  • substituted as used herein and hereafter denotes that the group it refers to is either unsubstituted or substituted independently with one or more, preferably 1, 2, 3 or 4, substituent(s) attached at any available atom to produce a stable compound.
  • phenyl may be substituted once with a denoted substituent attached to o-, m- or p- position of the phenyl ring.
  • substituted refers to a substituent group as defined herein in which one or more bonds to a hydrogen atom contained in the group if refers to are replaced by a bond to a non-hydrogen atom of the substituent unless otherwise denoted.
  • stereoisomer refers to stereoisomers of compounds.
  • stereoisomers include, but are not limited to, enantiomers, diastereomers, cis-trans- isomers, and ff-Z-isomers.
  • pharmaceutically acceptable salt refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typically, these are acid addition salts or base addition salts of the referred compounds of the invention.
  • acid addition salt includes any non-toxic organic and inorganic acid addition salts that that the compounds of formula (I)-(V), (la), (lb), (lc), (Id), (le), (If), (Ig), and (F) can form.
  • Illustrative inorganic acids, which form suitable acid addition salts include, but are not limited to, hydrogen chloride, hydrogen bromide, sulphuric and phosphoric acids.
  • Illustrative organic acids which form suitable acid addition salts, include, but are not limited to, acetic acid, lactic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, methane sulfonic acid, salicylic acid, and the like.
  • the term "acid addition salt” as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates, and the like. These salts also include salts useful for the chiral resolution of racemates.
  • base addition salt includes any non-toxic base addition salts that the compounds of formula (I)-(V), (la), (lb), (lc), (Id), (le), (If), (Ig), and (G) can form.
  • Suitable base addition salts include, but are not limited to, those derived from inorganic bases such as aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, and zinc salts, in particular sodium and ammonium salts.
  • organic base addition salts include salts of trialkylamines, such as triethyl amine and trimethyl amine, other salts of organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, morpholine, and the like, and choline salts.
  • compositions of the present invention may be administered in an effective amount within the dosage range of about 0.1 gg/kg to about 300 mg/kg, preferably between 1.0 gg/kg to 10 mg/kg body weight.
  • Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the term "effective amount" refers to an amount of a composition or a pharmaceutical composition that confers a therapeutic effect on the treated subject.
  • the therapeutic effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. subject gives an indication of or feels an effect).
  • Such treatment need not necessarily completely ameliorate the condition or disease. Further, such treatment or prevention can be used in conjunction with other traditional treatments for reducing the condition or disease known to those skilled in the art.
  • the effective amount will typically be determined by a physician, and depend on the condition or disease to be treated, the chosen route of administration, the actual compound administered, the age, gender, weight, and response of the individual patient, the severity of the patient's symptoms, and like.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention.
  • Suitable pharmaceutically acceptable excipients include, but are not limited to, the following types of excipients: diluents (for example starches, mannitol), fillers (for example lactose, microcrystalline cellulose or calcium hydrogen phosphate), binders (for example pre-gelatised corn starch, polyvinylpyrrolidone or methylcellulose), additives (for example magnesium stearate, talc, silica), disintegrants (for example potato starch), lubricants (for example sodium lauryl sulphate), glidants (for example fumed silica, talc, magnesium carbonate), granulating agents (for example water, ethanol), coating agents (for example hydroxypropyl methylcellulose, gelatin, waxes, shellac, plastics, plant fibers), wetting agents (for example sorbitan monopalmitate, poloxamer 407), solvents (for example water), co-solvents (for example ethanol, propylene glycol), suspending agents
  • Excipients and/or auxiliaries may facilitate processing of the active agent(s) into preparations that can be used pharmaceutically.
  • the skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the pharmaceutical composition and what other ingredients are present in the pharmaceutical composition.
  • compositions of the invention are most preferably used alone or in combination i.e. administered simultaneously, separately or sequentially with other active ingredients, e.g. pharmaceutically active compounds or biologic products.
  • active ingredients e.g. pharmaceutically active compounds or biologic products.
  • the amounts of the pharmaceutical composition(s) of the invention, particularly a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable salts thereof, and the other active ingredient(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • compositions of the invention may be administered by various routes, for example, parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, topical, and by intradermal injections, and via transdermal, rectal, buccal, oromucosal, nasal, ocular routes and via inhalation and via implant.
  • compositions may be formulated into suitable pharmaceutical formulations; suitable administration forms include, for example, solutions, dispersions, suspensions, powders, capsules, tablets, pills, controlled release capsules, controlled release tablets and controlled release pills.
  • suitable pharmaceutical formulations of the pharmaceutical compositions may contain one or more suitable pharmaceutically acceptable carrier (s).
  • pharmaceutically acceptable carrier refers to substrates comprised in pharmaceutical compositions for drug delivery, which serves to improve the selectivity, effectiveness, and/or safety of drug administration.
  • pharmaceutically acceptable carriers include, but are not limited to, pharmaceutically acceptable excipients, liposomes, (polymeric) micelles, microspheres, nanoparticles, and protein-drug conjugates.
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art.
  • Pharmaceutical compositions of the invention include, but are not limited to, for parenteral and topical administration that include, but are not limited to, sterile aqueous or non- aqueous solvents, suspensions and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oil, fish oil, and injectable organic esters.
  • Aqueous carriers include, but are not limited to, water, water- alcohol solutions, including saline and buffered medial parenteral vehicles including sodium chloride solution, Ringer’s dextrose solution, dextrose plus sodium chloride solution, Ringer’s solution containing lactose, or fixed oils.
  • Intravenous vehicles include, but are not limited to, fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer’s dextrose and the like.
  • Aqueous pharmaceutical compositions according to the invention may comprise suitable buffer agents, such as sodium and potassium phosphates, citrate, acetate, carbonate or glycine buffers depending on the targeted pH-range. The use of sodium chloride as a tonicity adjuster is also useful.
  • Pharmaceutical compositions may include other excipients, such as stabilizing agents or preservatives.
  • Useful stabilizing excipients include surfactants (polysorbate 20 & 80, poloxamer 407), polymers (polyethylene glycols, povidones), carbohydrates (sucrose, mannitol, glucose, lactose), alcohols (sorbitol, glycerol propylene glycol, ethylene glycol), suitable proteins (albumin), suitable amino acids (glycine, glutamic acid), fatty acids (ethanolamine), antioxidants (ascorbic acid, cysteine etc.), chelating agents (EDTA salts, histidine, aspartic acid) or metal ions (Ca, Ni, Mg, Mn).
  • the pharmaceutical composition according to the present invention may be provided in concentrated form or in form of a powder to be reconstituted on demand. In such cases formulations of powder for solution for injection/infusion excipients mentioned above may be used. In case of lyophilizing, certain cryoprotectants are preferred, including polymers (povidones, polyethylene glycol, dextran), sugars (sucrose, glucose, lactose), amino acids (glycine, arginine, glutamic acid) and albumin. If solution for reconstitution is added to the packaging, it may consist e.g., of pure water for injection or sodium chloride solution or dextrose or glucose solutions.
  • treatment or prevention includes prophylaxis, or prevention of, as well as lowering the individual's risk of falling ill with the named disorder or condition, or alleviation, amelioration, elimination, or cure of the said disorder once it has been established.
  • administering or “administered” to a subject or patient includes dispensing, delivering or applying the composition or pharmaceutical composition to the subject by any suitable route for delivery of the composition or pharmaceutical composition to a site in the body where desired.
  • Compounds of formula (I) of the present invention may be useful in therapy, especially in the treatment or prevention of CNS related diseases and conditions in animals, in particular mammals, and humans.
  • compounds of formula (I) possess pharmacological properties for the treatment and/or prophylaxis of CNS related diseases or conditions that include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, depression, anxiety, hyperactivity, narcolepsy, drug addiction, alcoholism, anorexia, bulimia, mitochondrial disease, obesity, and multiple sclerosis.
  • the compounds of formula (I) of the present invention bind to one or more protein involved in a CNS related disease or condition, wherein examples of the proteins include, but are not limited to, trace amine receptor, dopamine and serotonine receptors, their respective transporters and acyl and methyl transferases, norpinephrine transporter, monoamino-oxidases, catecholine-O- methylransferase, adrenergic receptors, tyrosine hydroxylase, histamine receptors, orexin receptors, NMDA-receptors, sigma-1 receptor, muscarinic and nicotinic acetylcholine receptors, opioid receptors, neuropeptide receptors, melanocortin receptors (excluding MC3R), neurokinin receptors and Corticotropin-releasing factor receptor 1 to name a few.
  • the proteins include, but are not limited to, trace amine receptor, dopamine and serotonine receptors, their respective transporters and
  • protected with a protecting group refers to an atom or a functional group that is covalently attached to, or has been modified by, a protecting group. Said protecting group enables chemoselectivity in a reaction, therefore, the protecting group protects an atom or a functional group from reacting in a reaction. It is to be understood that the protecting group protects the atom or functional group fully or partly, i.e. the atom or the functional group protected with a protecting group may react partly in a reaction. Skilled artisans possess the knowledge and skill in the art to enable them to select suitable protecting groups for the atoms or functional groups to be protected.
  • protecting groups there are a number of resources that are available to the skilled artisan which describe protecting groups and may be useful in selecting suitable protecting groups for the atoms or functional groups to be protected.
  • suitable protecting groups and methods to protect compounds with suitable protecting groups see, for example, Protective Groups in Organic Synthesis, 4th Edition, 2007, John Wiley & Sons, Inc., Hoboken, New Jersey.
  • Examples of atoms and functional groups that may be protected with protecting groups include, but are not limited to, optionally substituted 1H-indole, preferably the nitrogen of the 1H-indole, 0, S, N, OH, SH, NH2, carbonyls such as aldehydes and ketones, ethers, esters, and amides.
  • protecting groups include, but are not limited to, carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl, BOC, Fmoc, acetyl, benzoyl, phenyl, benzyl, trityl, sulfonyls such as phenylsulfonyl, tosyl (Ts), mesyl, and trifyl; tosylate, silyl ethers such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-z ' so-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers; tetrahydropyranyl (THP), p-methoxyphenyl ether (PMP), p-methoxybenzyl ether (PMB), b-methoxyethoxymethyl ether (MEM), pivaloyl, ace
  • the nitrogen of said 1H-indole is optionally protected with a protecting group
  • a protecting group refers to an optional protecting group that replaces the hydrogen of the nitrogen of 1H-indole wherein R 3 , R 4 , R 5 , and R 6 are as defined above and below, and therefore, said protecting group protects said nitrogen from reacting, and said 1H-indole is formed by R 1 and R 2 , together with the carbon atoms they are attached to, of the compound of formula (1) (said 1H-indole is fused at positions 2 and 3 (indicated with asterisks) with positions 4 and 5 of the substituted 1,2, 3, 6- tetrahydropyridines and 2,3-dihydropyridines and, therefore, forming compounds of the invention).
  • the oxygen or sulphur of said OH or SH is optionally protected with a protecting group
  • a protecting group refers herein and hereafter to an optional protecting group that replaces the hydrogen of said OH or SH and therefore, said protecting group protects said oxygen or sulphur.
  • activating group refers to a functional group of a compound that promotes a reaction to occur and/or has a positive influence of the overall reaction rate and/or have a directing effect on positional isomer of the products that are formed.
  • Said activating group may or may not be part of the formed product, i.e. it is to be understood that the activating group may be present in the product, or the activating group may be a leaving group, or part of the leaving group, in e.g. S N 2, S N I and addition-elimination reactions.
  • a compound disclosed herein may have one or more activating group (s) that may be the same or different.
  • activating groups include, but are not limited to, sulfonyls such as phenylsulfonyl, tosyl (Ts), mesyl, and trifyl; halogen, (substituted) amino groups, amides, esters, hydroxy, alkoxy, acyloxy, thiol, alkyl, (per)haloalkyl and photolabile groups.
  • aldehyde refers to a compound with an aldehyde functional group or a compound with a functional group that forms an aldehyde functional group.
  • aldehydes include, but are not limited to, acetaldehyde, esters and anhydrides of 4-oxobutanoate and 5- oxopentanoate, such as methyl 4-oxobutanoate and methyl 5-oxopentanoate, and 1,1 -diethoxy ethane (acetaldehyde diethyl acetal).
  • 1,1- diethoxyethane, and other masked aldehydes useable in a method of the invention forms acetaldehyde in situ in a ring formation reaction of a step of a method of the invention.
  • activating group reactant refers to a reactant, comprising an activating group, that reacts with a compound in a reaction to form a compound or an intermediate comprising said activating group. It is to be understand that there may be different activating group reactants comprising the same activating group.
  • the reaction may comprise one or more activating group reactant(s) that may be the same or different.
  • activating group reactants include, but are not limited to, sulfinic acids (sulfonyls) such as phenylsulfinic acid (phenylsulfonyl) and p-toluenesulfinic acid (tosyl); mesyl halides (mesyl) such as methanesulfonyl chloride (mesyl); trifyl azide (trifyl), trifluoromethanesulfonyl chloride (trifyl), halogens (X) such as Br2 (Br); trifluoroacetyl chloride (TFA), and trifluoroacetic anhydride (TFA).
  • sulfinic acids sulfonyls
  • mesyl halides such as methanesulfonyl chloride (mesyl)
  • trifyl azide trifyl
  • trifluoromethanesulfonyl chloride trifyl
  • activating agent refers to a substance or compound added to a reaction to cause a chemical reaction. Said activating agent may or may not be a catalyst. It is to be understood that said activating agent may or may not be consumed in the reaction. Examples of activating agents include, but are not limited to, Lewis acids such as TiCU, boron trifluoride, and boron trifluoride diethyl etherate.
  • a ring formation refers to a reaction wherein one or more cyclic structures of a compound is formed, wherein the formed compound has more (e.g. 1, 2, 3, or 4 more) cyclic structure (s) than the starting material compound (e.g. a compound of formula (!')).
  • the ring formation reaction may comprise one or more reactions (steps), i.e. the reaction may or may not first produce an intermediate compound, which may or may not be isolated, and said intermediate compound reacts further forming a compound with one or more cyclic structure(s), e.g. a compound of formula (1).
  • the compound with one or more cyclic structure (s) e.g.
  • a compound of formula (1) is formed by one or more ring formation reaction(s) of a one-pot reaction. Additionally, or alternatively, an intermediate compound of a short-lived intermediate is formed that produces a compound with one or more cyclic structure(s) (e.g. a compound of formula (1)).
  • deprotection reaction refers to a reaction, wherein a protecting group is removed from a compound.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable reactants or reagents for the deprotection reaction(s).
  • suitable reagents and reactants there are a number of resources that are available to the skilled artisan which describe suitable reagents and reactants and may be useful in selecting suitable reagents and reactants for the protecting groups to be deprotected.
  • suitable deprotecting reactions reactants and reagents, see, for example, Protective Groups in Organic Synthesis, 4th Edition, 2007, John Wiley & Sons, Inc., Hoboken, New Jersey.
  • Examples of reactants and reagents usable in the deprotection reaction(s) include, but are not limited to, tetra-n-butylammonium fluoride (TMS), 3 ⁇ 4 (benzyl), bases such as NaOH (acetyl), acids such as pyridinium p-toluenesulfonate and EtOH (THP), and 2,3-dichloro-5,6-dicyano-p-benzoquinone (PMB).
  • TMS tetra-n-butylammonium fluoride
  • 3 ⁇ 4 benzyl
  • bases such as NaOH (acetyl)
  • acids such as pyridinium p-toluenesulfonate and EtOH (THP)
  • PMB 2,3-dichloro-5,6-dicyano-p-benzoquinone
  • the present invention provides a novel compound of formula (1) wherein the dotted line represents an optional bond; R 1 and R 2 , together with the carbon atoms they are attached to, form a group selected from a 1H-indole group and a benzene group, and said 1H-indole group and benzene group being optionally substituted with one to four substituent(s) each independently selected from the group consisting of R 3 , R 4 , R 5 , and R 6 , wherein each R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of halogen, OH, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, C1-3- (per)haloalkoxy;
  • R a and R b together with the carbon atom and nitrogen atom they are attached to, form a group selected from a 5- and 6-membered cyclic amide, and R c is H; or R a is Me, and
  • R b and R c together with the nitrogen atom and carbon atom they are attached to, form a group selected from a 5- and 6-membered cyclic amide; or R a is Me,
  • R b is H, or R b is absent when the dotted line represents a bond, and R c is H, provided that R 1 and R 2 , together with the carbon atoms they are attached to, form said optionally substituted 1H-indole group;
  • R 7 is selected from the group consisting of halogen, OH, oxo, SH, NOR 8 , C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy, CN, C(0)N(R 8 )2, and N(R 8 )2, or R 7 may also be C 1-4 -alkyl with the provisio that said 1H-indole group or benzene group is substituted with one to four substituent(s) each independently selected from the group consisting of halogen, OH, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy, or
  • R 7 may also be H provided that when R a and R b , together with the carbon atom and nitrogen atom they are attached to, form a group selected from a 5- and 6-membered cyclic amide, R c is H, then R 4 and R 5 is each independently selected from the group consisting of halogen, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, and C 1-3 -(per)haloalkoxy, or when R a is Me, R b and R c , together with the carbon atom and nitrogen atom they are attached to, form a 6-membered cyclic amide, then R 1 and R 2 , together with the carbon atoms they are attached to, form said optionally substituted l/f-indole group, or when R a is Me, R b and R c , together with the carbon atom and nitrogen atom they are attached to, form a 5-membered cyclic amide, and R 1 and R 2 , together with
  • the dotted line represents an optional bond
  • the dotted line refers to a bond that may or may not be present. It is to be understood that when the dotted line is present then it forms, together with the single bond next to it, a double bond and therefore, the compound of formula (1) is equal to a compound of formula (11) and when the dotted line is not present, the compound of formula (1) is equal to a compound of formula (111)
  • benzene group refers to benzene, which is fused with the carbons that R 1 and R 2 of the compound of formula (1) are attached to. Therefore, term “R 1 and R 2 , together with the carbon atoms they are attached to, form a group selected from a 1H-indole group and a benzene group” as used herein and hereafter refers to a 1H-indole ring and a benzene ring fused with derivatives of 1,2,3,6-tetrahydropyridine and 2,3- dihydropyridine of the invention.
  • a compound of formula (1) is equal to a compound of formula (IV) wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b , R c , and the dotted line are as defined above, and when R 1 and R 2 , together with the carbon atoms they are attached to, form a benzene group, then a compound formula (1) is equal to a compound of formula (V) wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b , R c , and the dotted line are as defined above.
  • the compound has formula (la), (lb), or wherein
  • R a and R b together with the carbon atom and nitrogen atom they are attached to, form a group selected from a 5- and 6-membered cyclic amide, and R c is H; or R a is Me, and R b and R c , together with the nitrogen atom and carbon atom they are attached to, form a group selected from a 5- and 6-membered cyclic amide;
  • R d is H, or R d is absent when the dotted line represents a bond
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and the dotted line are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (Ic), (Id), (le), (If), or (Ig) wherein m is 1 or 2; n is 1 or 2;
  • R d is H, or R d is absent when the dotted line represents a bond; and the dotted line, R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof. Furthermore, selection of the substituents R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is particularly important for attaining the desired properties of the compounds of the present invention.
  • the compound has formula (Id), (le), (If), or (Ig)
  • m is 1 or 2; n is 1 or 2; and R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • selection of the substituents R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is particularly important for attaining the desired properties of the compounds of the present invention. Additionally, or alternatively, selection of m, and n is particularly important for attaining the desired properties of the compounds of the present invention.
  • the compound has formula (Id), or (If), preferably (Id), wherein n is 1 or 2, preferably 1; and R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (Id) and n is 1.
  • selection of the substituents R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is particularly important for attaining the desired properties of the compounds of the present invention.
  • the compound has formula (le), or (Ig), preferably (Ig), wherein m is 1 or 2, preferably 1; and
  • R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (Ig) and m is 1.
  • selection of the substituents R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is particularly important for attaining the desired properties of the compounds of the present invention.
  • the compound has formula (Ic), wherein
  • R d is H, or R d is absent when the dotted line represents a bond; and the dotted line, R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (I), wherein
  • R 1 and R 2 together with the carbon atoms they are attached to, form a group selected from a l/f-indole group, and said l/f-indole group being optionally substituted with one to four substituent(s) each independently selected from the group consisting of R 3 , R 4 , R 5 , and R 6 , wherein each R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of halogen, OH, C 1-4 -alkyl, C 1-3 - (per)haloalkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy;
  • R a is Me
  • R b is H, or R b is absent when the dotted line represents a bond, preferably R b is H;
  • R c is H; and the dotted line, R 7 , and R 8 are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (I), (Ic), (Id), (Ie), (If), or (Ig), wherein
  • R 3 and R 6 are each independently selected from the group consisting of H, halogen, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, and C 1-3 -(per)haloalkoxy, preferably each independently selected from H and F;
  • R 4 and R 5 are both halogen, preferably F, or one of R 4 and R 5 is halogen, preferably F, and the other is C 1-4 -alkyl, C 1-3 -(per)haloalkyl, or C 1-3 -(per)haloalkoxy, preferably methoxy, methyl, or trifluoromethyl;
  • R 7 is selected from the group consisting of H, halogen, OH, oxo, NOR 8 , Ci- 4 -alkyl, C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, and C 1-3 -(per)haloalkoxy, preferably H, F, OH, or methoxy, most preferably F; and the dotted line, R 1 , R 2 , R a , R b , R c , R d , and R 8 are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (1), (lc), (Id), (le), (If), or (Ig), wherein
  • R 3 and R 6 are each independently selected from the group consisting of H, halogen, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, and C 1-3 -(per)haloalkoxy, preferably each independently selected from H and F, most preferably H;
  • R 4 and R 5 are both F, or one of R 4 and R 5 is F and the other is C 1-4 -alkyl or C 1-3 -(per)haloalkyl, preferably both are F;
  • R 7 is selected from the group consisting of H, halogen, OH, oxo, NOR 8 , Ci- 4 -alkyl, C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, and C 1-3 -(per)haloalkoxy, preferably H, F, OH, or methoxy, most preferably F; and the dotted line, R 1 , R 2 , R a , R b , R c , R d , and R 8 are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (1), (lc), (Id), (le), (If), or (Ig), wherein
  • R 3 and R 6 are each independently selected from the group consisting of H, halogen, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, and C 1-3 -(per)haloalkoxy, preferably each independently selected from H and F, most preferably H;
  • R 4 and R 5 are both F, or one of R 4 and R 5 is halogen, preferably F, and the other is H, C 1-4 -alkyl or C 1-3 -(per)haloalkyl, preferably one of R 4 and R 5 is halogen and the other is H;
  • R 7 is selected from the group consisting of halogen, OH, C 1-3 -alkoxy, Ci- 3 -(per)haloalkoxy, preferably F, OH, methoxy, and ethoxy, most preferably F; and the dotted line, R 1 , R 2 , R a , R b , R c , R d , and R 8 are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • R 4 and R 5 are both halogen, preferably F.
  • R 4 is H
  • R 5 is halogen, preferably F
  • R 7 is selected from the group consisting of halogen, preferably F and OH.
  • R 4 is halogen, preferably F
  • R 5 is H
  • R 7 is selected from the group consisting of halogen, preferably F and OH.
  • the compound has formula (1), (Ic), (Id), (le), (If), or (Ig), wherein
  • R 3 and R 6 are each independently selected from H and halogen, preferably each independently selected from H and F;
  • R 4 and R 5 are both F, or one of R 4 and R 5 is F and the other is C 1-4 -alkyl or C 1-3 -(per)haloalkyl, preferably both are F; and
  • R 7 is selected from the group consisting of H, F, OH, C 1-4 -alkyl, and methoxy, preferably H, F, OH, or methoxy, more preferably H, or F, most preferably F; and the dotted line, R 1 , R 2 , R a , R b , R c , R d , and R 8 are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (Ic), (Id), (Ie), (If), or (Ig), wherein m is 1 or 2, preferably 1; n is 1 or 2, preferably 1;
  • R 3 and R 6 are each independently selected from the group consisting of H, halogen, OH, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy, preferably each independently selected from H, F, meyhoxy, ethoxy, more preferably each independently selected from H and F;
  • R 4 and R 5 are both halogen, preferably F, or one of R 4 and R 5 is halogen, preferably F, and the other is H, C 1-3 -alkoxy, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, or C 1-3 - (per)haloalkoxy, preferably H, methoxy, methyl, or trifluoromethyl, most preferably H;
  • R 7 is selected from the group consisting of halogen, OH, oxo, NOR 8 , C 1-4 - alkyl, C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, and C 1-3 -(per)haloalkoxy, preferably H, F, OH, or methoxy, most preferably F; and
  • R 8 , R d , and R 8 are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (Ie), or (Ig), wherein m is 1;
  • R 3 and R 6 are each independently selected from the group consisting of H, halogen, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, and C 1-3 -(per)haloalkoxy, preferably each independently selected from H and F;
  • R 4 and R 5 are both halogen, preferably F, or one of R 4 and R 5 is halogen, preferably F, and the other is H, C 1-3 -alkoxy, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, or C 1-3 - (per)haloalkoxy, preferably H, methoxy, methyl, or trifluoromethyl, most preferably H;
  • R 7 is selected from the group consisting of H, halogen, OH, oxo, NOR 8 , Ci- 4 -alkyl, C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, and C 1-3 -(per)haloalkoxy, preferably H, F, OH, or methoxy, most preferably F; and
  • R 8 are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (Id), or (If), wherein n is 1 or 2, preferably 1;
  • R 3 and R 6 are each independently selected from the group consisting of H, halogen, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, and C 1-3 -(per)haloalkoxy, preferably each independently selected from H and F;
  • R 4 and R 5 are both halogen, preferably F, or one of R 4 and R 5 is halogen, preferably F, and the other is C 1-4 -alkyl, C 1-3 -(per)haloalkyl, or C 1-3 -(per)haloalkoxy, preferably methyl, trifluoromethyl, or trifluoromethoxy, most preferably trifluoromethyl;
  • R 7 is selected from the group consisting of H, halogen, OH, oxo, NOR 8 , Ci- 4 -alkyl, C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, and C 1-3 -(per)haloalkoxy, preferably H, F, OH, or methoxy, most preferably F; and
  • R 8 is as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (lc), wherein
  • R 3 and R 6 are each independently selected from the group consisting of H, halogen, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, and C 1-3 -(per)haloalkoxy, preferably each independently selected from H and F;
  • R 4 and R 5 are both halogen, preferably F, or one of R 4 and R 5 is halogen, preferably F, and the other is C 1-4 -alkyl, C 1-3 -(per)haloalkyl, or C 1-3 -(per)haloalkoxy, preferably methyl, trifluoromethyl, or trifluoromethoxy, most preferably trifluoromethyl;
  • R 7 is selected from the group consisting of H, halogen, OH, oxo, NOR 8 , Ci- 4 -alkyl, C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, and C 1-3 -(per)haloalkoxy, preferably H, F, OH, or methoxy, most preferably F;
  • R b is H, or R b is absent when the dotted line represents a bond, preferably R b is H;
  • R 8 is as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (lc), wherein R 3 and R 6 are each independently selected from the group consisting of H, halogen, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, and C 1-3 -(per)haloalkoxy, preferably each independently selected from H and F;
  • R 4 and R 5 are both halogen, preferably F, or one of R 4 and R 5 is halogen, preferably F, and the other is H, C 1-4 -alkyl, C 1-3 -(per)haloalkyl, or C 1-3 - (per)haloalkoxy, preferably H, methyl, trifluoromethyl, or trifluoromethoxy, most preferably H;
  • R 7 is selected from the group consisting of halogen, OH, oxo, NOR 8 , C 1-3 - alkoxy, and C 1-3 -(per)haloalkoxy, preferably H, F, OH, or methoxy, most preferably F;
  • R b is H, or R b is absent when the dotted line represents a bond, preferably R b is H;
  • R 8 is as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (1), (lc), (Id), (le), (If), or (Ig), wherein
  • R 3 , R 6 , and R 7 are H
  • R 4 and R 5 are F; and the dotted line, R 1 , R 2 , R a , R b , R c , and R d , are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (Id), (le), (If), or (Ig), more preferably (le), or (Ig), most preferably (Ig), wherein R 3 , R 6 , and R 7 are H; and R 4 and R 5 are F; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (1), (lc), (Id), (le), (If), or (Ig), wherein
  • R 3 and R 6 are H
  • R 4 , R 5 and R 7 are F; and the dotted line, R 1 , R 2 , R a , R b , R c , and R d , are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (1), (Id), (le), (If), or (Ig), wherein
  • R 3 and R 6 are H
  • R 4 , R 5 and R 7 are F
  • R a is Me
  • R b and R c together with the nitrogen atom and carbon atom they are attached to, form a group selected from a 5- and 6-membered cyclic amide; and R 1 , and R 2 are as defined above; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (Id), (Ie), (If), or (Ig), more preferably (Ie), or (Ig), most preferably (Ig), wherein R 3 and R 6 are H;
  • R 4 , R 5 and R 7 are F; m is 1 or 2, preferably 1; and n is 1 or 2, preferably 1; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound has formula (Ig), wherein m is 1;
  • R 3 and R 6 are H; and R 4 , R 5 and R 7 are F; or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I), (la), (lb), (Ic), (Id), (Ie), (If), or (Ig) is selected from the group consisting of:
  • a pharmaceutical composition comprising an effective amount of one or more compounds of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipient(s).
  • compositions of the present disclosure comprise an effective amount of one or more compounds of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carrier (s). Therefore, in embodiments, pharmaceutical compositions comprise an effective amount of one or more compounds of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipient(s) and/or one or more pharmaceutically acceptable carrier(s), or any combination thereof.
  • pharmaceutical compositions comprise one compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, preferably a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipient(s) and one pharmaceutically acceptable carrier.
  • compositions of the present disclosure comprise an effective amount of one or more compounds of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, in combination with one or more other active ingredient(s). Therefore, in embodiments, pharmaceutical compositions comprise an effective amount of one or more compounds of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipient(s) and/or one or more pharmaceutically acceptable carrier(s) and/or one or more other active ingredient(s), or any combination thereof.
  • compositions consist an effective amount of one or more compounds of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, preferably a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipient(s), preferably 1, 2, or 3 pharmaceutically acceptable excipient(s), more preferably 1 pharmaceutically acceptable excipient.
  • compositions consist an effective amount of one or more compounds of formula (I), preferably an effective amount of 1 or 2 compounds of formula (1), more preferably 1 compound of formula (1), or a stereoisomer or a pharmaceutically acceptable salt thereof, preferably a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipient(s), preferably 1, 2, or 3 pharmaceutically acceptable excipient(s), and/or one or more pharmaceutically acceptable carrier(s), preferably 1, 2, or 3 pharmaceutically acceptable carrier(s), more preferably 1 pharmaceutically acceptable carrier.
  • compositions consist an effective amount of one or more compounds of formula (1), preferably an effective amount of 1 or 2 compounds of formula (1), more preferably 1 compound of formula (1), or a stereoisomer or a pharmaceutically acceptable salt thereof, preferably a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipient(s), preferably 1, 2, or 3 pharmaceutically acceptable excipient(s), and/or one or more pharmaceutically acceptable carrier(s), preferably 1, 2, or 3 pharmaceutically acceptable carrier(s), more preferably 1 pharmaceutically acceptable carrier, and/or one or more other active ingredient(s), preferably one other active ingredient.
  • a compound of formula (1) or a stereoisomer or pharmaceutically acceptable salt thereof, for use as a medicament.
  • a compound of formula (1) or a stereoisomer or pharmaceutically acceptable salt thereof, for use in treatment or prevention of CNS related diseases or conditions.
  • a compound of formula (1) for use in the treatment or prevention of a disease or condition selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, depression, anxiety, hyperactivity, narcolepsy, drug addiction, alcoholism, anorexia, bulimia, and mitochondrial disease.
  • methods for the preparation of a compound of formula (I), or pharmaceutically acceptable salt or a stereoisomer thereof comprising the steps of: providing a compound of formula (G) wherein R 1 , R 2 , and R 7 are as defined herein and hereafter, wherein when R 1 and R 2 , together with the carbon atoms they are attached to, form a 1H-indole group, then the nitrogen of said 1H-indole group is optionally protected with a protecting group, wherein when R 7 is OH or SH, then the oxygen or sulphur of said OH or SH is optionally protected with a protecting group,
  • R b' and R c together with the carbon atom and nitrogen atom they are attached to, form a group selected from a 5- and 6-membered cyclic amide, or R b' is H or activating group, and R c” is H; reacting said compound of formula (G) with an aldehyde, optionally in the presence of one or more activating group reactant(s), which/that optionally together with one or more activating agent(s) facilitate (s) a ring formation; optionally performing one or more deprotection reaction(s); to obtain the compound of formula (I) wherein R 1 , R 2 , R 7 , R a , R b , R c , and the dotted line are as defined herein and hereafter; and optionally converting the compound of formula (I) to a pharmaceutically acceptable salt thereof.
  • the method for the preparation of a compound of formula (1), or pharmaceutically acceptable salt or a stereoisomer thereof further comprises the step of: converting the compound of formula (1) to another stereoisomer thereof, wherein said step is performed before or after the step of optionally converting the compound of formula (1) to a pharmaceutically acceptable salt thereof.
  • the aldehyde is selected from the group consisting of acetaldehyde, methyl 4- oxobutanoate, methyl 5-oxopentanoate, and 1,1-diethoxyethane.
  • the step of reacting compound of formula (G) with an aldehyde optionally further comprises one or more aldehydes, and optionally of one or more steps of separating and/or purifying one or more compound(s) of formula (1).
  • the compounds of the invention can be synthesized using well documented reactions and commercially available starting materials. We have explored a series of new T1Q analogues primarily targeted to mimic the actions of IMeTIQ and also SAL to some extent. These novel compounds can be used to achieve many desirable pharmacological responses. Fluorination can alter the bond strength, lipophilicity, conformation, electrostatic potential, dipoles, and pKa. Substitution, especially fluorination, at the position of metabolic attack - mainly at positions corresponding to substituents R 4 , R 5 , and R 7 of compounds having formula (la), (lb), and (lc) - is used to alter the route and rate of metabolic degradation. Fluorination may also alter the tissue distribution, pharmacodynamics, and toxicology of the compound. It can be generalized that replacing hydrogen with fluorine causes minimal steric effects at the receptor.
  • the compounds of the present invention are actively transported over the blood brain barrier by organic cation transporters and are concentrated in the brain. Most of the compounds of the present invention cannot be oxidized to form epoxides thereby making them less prone to cause oxidative stress.
  • the compounds of the invention are associated with neuroprotective and neuroregenerative properties instead of neurotoxicity or neurodegeneration, which is the case with SAL. Further, the novel compounds are better in mimicking desirable effects of SAL and treating alcoholism and Parkinson’s disease than e.g. 6-monofluorinated T1Q.
  • novel compounds according to the invention show structural similarities to IMeTIQ.
  • the novel compounds can be used, in addition to the treatment of e.g. Alzheimer’s disease and Parkinson’s disease, to treat or prevent addictions in general - from alcohol to cocaine and heroin. Number of positive pharmacological responses can be achieved simultaneously. While decreasing the tendency to relapse and likelihood of developing an addiction, these compounds can act as general mood stabilizers and general neuroprotectants possessing remarkable antiparkinsonian and antiepileptic character.
  • the compounds exhibit many pharmacological responses, such as prolonging the duration of morphine without enhancing the peak action; antagonizing the development of morphine tolerance; reducing the naloxone-precipitated withdrawal symptoms; inhibiting the reinstatement of cocaine self-administration; attenuating cravings, inhibiting the activity of monoamine-oxidases (MAOs); inhibiting the activity of acetylcholinesterase (ACE); affecting the activity of one or more of trace amine receptor, dopamine receptors and transporter, serotonine receptors and transporter, serotonine acyl and methyltransferases, norepinephrine transporter, monoamino-oxidases, catecholine-O- methyltransferase, and shifting metabolism towards it; adrenergic receptors, tyrosine hydroxylase, histamine receptors, orexin receptors, NMDA-receptors, sigma 1 -receptor, muscarinic and nicotinic
  • the invention may also be for use in the treatment or prevention of a disease or condition associated with HIV transcriptase.
  • compounds of formula (I) may be used as synthesis intermediates for the preparation of other compounds, in particular of other pharmaceutically active compositions, which are obtainable from compounds of formula (I) and, for example by introduction of substituents or modification of functional moieties.
  • the compounds and pharmaceutical compositions of the invention may also be useful in medical devices and medical kits.
  • the compounds according to the present invention may be prepared by processes known per se as follows.
  • the following examples illustrate the preparation of compounds of formula (I).
  • Step 1 1.0 mol eq. optionally subst. benzaldehyde, 1.2 mol eq. nitromethane, 0.47 mol eq. ammonium acetate and 0.35 mol eq. glacial acetic acid (GAA) was sonicated (40 kHz) at RT for 3 h. After removal of nitromethane, partition between dichloromethane and water then brine gave a crude product which was recrystallized from aq, (m) ethanol or AcOH; or
  • Step 2 Sulfonating the aliphatic OH-group to appropriate sulfonyl ester by stirring 1.0 mol eq. of subst. nitroalcohol in DCM with 1.2 mol eq. of triethylamine (or using pyridine for the solvent) and adding slowly 1.1 mol eq. of p-toluenesulfonyl chloride maintaining the temperature at -5°C until conversion was complete. The product was washed several times with brine, dried over anhydrous MgSCU and concentrated in vacuo.
  • Step 3 (in the case of R 7 -halogen substitution) Modified Finkelstein reaction to the sulfonate ester with potassium halide (in this case KF) proceeded by dissolving 1 mol eq. of sulfonyl-intermediate from the step 2 with 6 ml of acetonitrile per gram of substrate, 0.5 mol eq. of l-butyl-3-methylimidazolium tetrafluoroborate and 5 mol eq. of H2O which after 1.05 mol eq. amount of KF was added and the solution was mixed and sonicated at RT for 180 min or until TLC showed completion.
  • the R 7 -halogen substituted compounds were then extracted with DCM and washed several times with brine, dried over anhydrous MgSCU and concentrated in vacuo prior proceeding.
  • Step 4 In the case of protected R 7 -OH groups, the synthesis proceeds via nitroalcohol intermediate:
  • platinum(IV) oxide PtOz
  • Raney nickel Raney nickel
  • Platinum on carbon Pt/C
  • Step 1 A synthesis method from Tetrahedron: Asymmetry 14 (2003)
  • Step 3 In the case of protected R 7 -OH groups, the R 7 -OH protecting groups were removed according to procedures well known in the art, e.g. in the case of O-trimethylsilyl protected compounds, otherwise skip this step:
  • Step 4 In the case of R 7 -SH group, otherwise skip this step:
  • step 3 The product from step 3 was converted to the tosylate following step 2 of the general procedure A.
  • the crude product was purified by column chromatography (hexane/ethyl acetate, 7:3 to 1:10) to give the thiol.
  • R 7 -SH group In the case of R 7 -SH group; general procedure D, step 4, was followed using the deprotected R 7 - OH compound.
  • R 7 -SH group In the case of R 7 -SH group; general procedure D, step 4, was followed using the deprotected R 7 -OH compound.
  • Step 2 The reaction mixture was partitioned between ethyl acetate (10 mL / 1 g substrate) and water (10 mL / 1 g substrate), separated, and the organic layer was washed twice with saturated sodium bicarbonate and dried over sodium sulfate (NazSCU). The drying agent was filtered off and the filtrate was distilled under reduced pressure to yield the desired compound.
  • R 7 - SH group general procedure D, step 4, was followed using the deprotected R 7 -OH compound.
  • acetolactate synthase converts an optionally subst. benzaldehyde (e.g. 3,4-difluorobenzaldehyde) to an optionally subst. 2-hydroxy-2- phenylacetaldehyde (e.g.
  • the products may be purified according to procedures well known in the art.
  • the R 7 -OH may be converted to a halogen, OH, oxo, SH, NOR 8 , C 1-3 -(per)haloalkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy, CN, C(0)N(R 8 ) 2 , or N(R 8 )z by synthesis methods described herein or conventional processes well-known to the person skilled in the art.
  • the one-pot chemoenzymatic reaction cascade method can also be used to synthesize other compounds with formula (I), (la), (lb), (Ic), (Id), (Ie), (If), and (Ig) of the invention. Therefore, e.g. an optionally subst. l//-indole-3-carbaldehyde or an optionally subst. iV-protected l//-indole-3-carboxaldehyde (e.g.
  • 1-benzyl-l H- indole-3-carboxaldehyde or l-(triisopropylsilyl)-l//-indole-3-carbaldehyde) may be used as a starting material in the one-pot chemoenzymatic synthesis method to give optionally subst. l,2,5,6,ll,llb-hexahydro-3//-indolizino[8,7-b]indol-3-ones and 2,3,6,7,12,12b-hexahydroindolo[2,3-a]quinolizin-4(l//)-ones:
  • the one-pot chemoenzymatic synthesis method may also comprise other enzymes, depending on the compound to be synthesized.
  • one or more intermediate products e.g. an optionally subst. phenethylamine or an optionally subst. 2-(l//-indol-3-yl)ethan-l-amine
  • the method may be used on a reaction product of one or more of the above disclosed chemical methods for the preparation of compounds.
  • 2-hydroxy-2- phenylacetaldehyde produced by an enzymatic reaction may be isolated, optionally purified, and may be converted to the 2-fluoro-2-phenylacetaldehyde as described in general procedure A.
  • the formed 2-fluoro-2-phenylacetaldehyde may thereafter be subjected to a one-pot chemoenzymatic synthesis method to give 6-fluoro- l,5,6,10b-tetrahydropyrrolo[2,l-a]isoquinolin-3(2//)-one.
  • protecting groups may be inserted by chemical reactions on products produced, optionally isolated, and thereafter subjected to a one-pot chemoenzymatic synthesis method. Additionally, the compounds may be deprotected from protecting groups after the final enzymatic reaction, or alternatively before, at or after any step of the enzymatic reactions.
  • One or more expression plasmid comprising genes encoding for the required enzymatic activities in functional linkage with the required regulatory sequences may be used in the one-pot chemoenzymatic synthesis method.
  • a single plasmid comprising all genes for the required enzymatic activities represents a particular convenient embodiment.
  • a plasmid suitable for use in such a method is exemplified in SEQ ID NO: 1 shown in the sequence protocol, which forms part of the present disclosure.
  • said one or more plasmid encodes for acetolactate synthase activity (e.g., AHAS 1, further exemplified by nucleotides 1142 to 3097 of SEQ ID NO: 1), for an enzyme with EC 2.6.1 activity (e.g.
  • transaminase for example transaminase E1V913_HALED, in particular as further exemplified in nucleotides 4603 to 5985 of SEQ ID NO: 1), for an enzyme with salsolinol synthase activity (in particular as further exemplified in nucleotides 6779 to 7009 of SEQ ID NO: 1), for an enzyme with EC 4.2.1.78 activity (e.g. a suitable norcolaurine synthase, such as the norcolaurine synthase as exemplified in nucleotides 10117 to 10689 of SEQ ID NO: 1), and for an enzyme with EC 2.1.1.28 activity (e.g. a suitable phenylethanolamine N-methyltransferase (PNMT), such as the P11086 PNMT, as further exemplified in nucleotides 14784 to 15335 of SEQ ID NO: 1.
  • PNMT phenylethanolamine N-methyltransferas
  • the regulatory sequences comprise sequences required to bring about the expression, translation and secretion of the enzymes, such as enhancers, promoters, sequences encoding for signal peptides (such as for the AmyE signal peptide, sortase cleavage signal, or PrsA), terminators, 5’ untranslated regions (5’ UTR), 3’ untranslated regions (3’ UTR), and transcription regulatory sequences (e.g. of the arabinose operon or the CUP operon).
  • the plasmid will also comprise additional sequences required for maintenance of the plasmid, for example a replication origin (e.g., oriU) and/or a reporter or selection gene (such as the mRaspberry reporter). Examples of such sequences are shown in SEQ ID NO: 1.
  • a replication origin e.g., oriU
  • a reporter or selection gene such as the mRaspberry reporter
  • Any suitable host which is compatible with the selected sequences and codon usage of the plasmid may be used.
  • a suitable Bacillus strain such as a suitable Bacillus subtilis strain
  • Bacillus subtilis (WB-600) may be used as the electrocompetent host.
  • Methods for introducing the plasmid into the host cell are generally known to the skilled person and are provided in reference text-books.
  • the host cell comprising the plasmid, such that the enzymatic activities are expressed and secreted in the environment of the host cell may then be used in the one-pot chemoenzymatic synthesis method.
  • the host cell may be used directly in the synthesis method, or only the supernatant of a fermentation of said host cell. Suitable fermentation procedures are also known to the skilled person, and publicly available, for example from catalogues of cell culture collections, and depend on the selected host cell.
  • the pharmaceutically acceptable salts of the compounds of formula (1) may be prepared by conventional processes well-known to the person skilled in the art.
  • diluents and expedients used in the preparation see, for example, Remington's Pharmaceutical Sciences, 20th Edition, 2000, Marck Publishing Company, Easton, Pennsylvania.
  • the pharmacological activity of the compounds of the invention can be verified by methods known in the art.
  • the reducing effect on alcohol seeking behavior can be verified using the procedure described by Heidbreder, C.A., et al., Addict Biol. 2007 Mar;12(l):35-50.
  • the parkinsonism-preventing activity can be shown, for example, as described by Okuda, K., et al. Biol Pharm Bull. 2006 Jul;29(7): 1401-1403.
  • the following specific non-limiting examples will further identify the compounds of the invention.
  • the general procedure B was used starting from 5-fluoro-l//-indole-3- carbaldehyde, followed by general procedures C and H.
  • the general procedure B was used starting from 4,6-difluoro-l//-indole-3- carbaldehyde, followed by general procedure G.
  • COMPOUND 10 4,5,6,7-Tetrafluoro-l-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole
  • the general procedure B was used starting from 4,5,6-trifluoro-l//-indole-3- carbaldehyde, followed by general procedures C and H.
  • COMPOUND 22 (57?,lla5)-9-Fluoro-5-methyl-l,2,5,6,ll,lla-hexahydro-3fMndolizino[6,7- ft]indol-3-one
  • COMPOUND 42 (5S,10R,10aR)-7,8,10-Trifluoro-5-methyl-l,5,10,10a-tetrahydropyrrolo[l,2- b]isoquinolin-3(2H)-one
  • the general procedure D was used starting from 5-[(R)-(3,4- difluorophenyl) (fluoro) methyl] pyrrolidin-2 -one.
  • the search space (C,U,Z) -coordinates for PDB ID lbp3 and protein homolog ClassA_5htla_human_Active_6G79_2018-07-10_GPCRDB were (13.730, 30.880, 13.170) and (91.84457623, 54.99481, 63.31365), respectively.
  • the PDB IDs and the protein homolog codes of proteins used in the calculations of the compounds of the invention are listed in Table 1 and results of the calculations are presented in Table 2. Table 1.
  • Table 1 The PDB IDs and the protein homolog codes of proteins used in the calculations of binding affinities of the compounds of the invention.
  • the compound with strongest binding affinity for dopamine transporter is (7R,12bR)-7,8,9,10-tetrafluoro-lH,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3- a]quinolizin-4-one (40).
  • the compound with strongest binding affinity for norepinephrine transporter is (12bS)-8,9-difluoro-lH,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one
  • the compound with strongest binding affinity for phenylethanolamine N- methyltransferase is 7,8-difluoro-5-methyl-l,5,10,10a-tetrahydropyrrolo[l,2- b]isoquinolin-3(2H)-one (17), preferably the (5S,10aR)-7,8-difluoro-5-methyl- l,5,10,10a-tetrahydropyrrolo[l,2-b]isoquinolin-3(2H)-one isomer.
  • the compound with strongest binding affinity for serotonin transporter is (7S,12bS)-7,8,9-trifluoro-lH,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin- 4-one (30).
  • the compound with strongest binding affinity for serotonin N-acetyltransferase is (7R,12bS)-7,8,9,10-tetrafluoro-lH,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3- a]quinolizin-4-one (39).
  • the compound with strongest binding affinity for N-acetylserotonin methyltransferase is (5S,10R,10aS)-7,8,10-trifluoro-5-methyl-l,5,10,10a- tetrahydropyrrolo [ 1,2 -b] isoquinolin-3 (2 H) -one (43) .
  • the compound with strongest binding affinity for 5-HT1A receptor is (7R,12bR)-
  • 7,8,9-trifluoro-lH,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (29).
  • the compound with strongest binding affinity for 5-HT2A receptor is 7,8,9,10- tetrafluoro-lH,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (7), preferably the (7S,12bS)-7,8,9,10-tetrafluoro-lH,2H,3H,4H,6H,7H,12H,12bH- indolo[2,3-a]quinolizin-4-one isomer.
  • the compound with strongest binding affinity for 5-HT1B receptor is (12bS)-8,9- difluoro-lH,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (27).
  • the compound with strongest binding affinity for 5-HT2B receptor is (7R,12bS)-
  • the compound with strongest binding affinity for 5-HT3 receptor is (4S)-4,6- difluoro-l-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (24).
  • the compound with strongest binding affinity for monoamino-oxidase A is 7,10- difluoro-5-methyl-l,5,10,10a-tetrahydropyrrolo[l,2-b]isoquinolin-3(2H)-one (15), preferably the (5R,10R,10aS)-7,10-difluoro-5-methyl-l,5,10,10a- tetrahydropyrrolo[l,2-b]isoquinolin-3(2H)-one isomer.
  • the compound with strongest binding affinity for monoamino-oxidase B is (1S,4S)- 4,6-difluoro-l-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole (4).
  • the compound with strongest binding affinity for alpha-2C adrenergic receptor is 5,6,7-trifluoro-l-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (12).
  • the compound with strongest binding affinity for beta-1 adrenergic receptor is (5S, 10S,10aR)-8, 10-difluoro-5-methyl-l, 5,10, lOa-tetrahydropyrrolo [1,2- b]isoquinolin-3(2H)-one (33).
  • the compound with strongest binding affinity for beta-2 adrenergic receptor is (lR,4R)-4,6,7-trifluoro-l-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole (34).
  • the compound with strongest binding affinity for phenylalanine hydroxylase is (lR,4R)-4,6,7-trifluoro-l-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole (34).
  • the compound with strongest binding affinity for tyrosine hydroxylase is (7S,12bS)-7,8,9-trifluoro-lH,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-
  • the compound with strongest binding affinity for 0X2 orexin receptor is (7R,12bS)-7,8,9-trifluoro-lH,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin- 4-one (31).
  • the compound with strongest binding affinity for prolactin receptor is (7R,12bR)- 7,8,9-trifluoro-lH,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (29).
  • the compound with strongest binding affinity for NMDA receptor GluNl is (5R,6R,10bS)-6,9-difluoro-5-methyl-l,5,6,10b-tetrahydropyrrolo[2,l- a]isoquinolin-3(2H)-one (37).
  • the compound with strongest binding affinity for NMDA receptor Glu2B is 4,5,6,7- tetrafluoro-l-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole (10), preferably the (lS,4R)-4,5,6,7-tetrafluoro-l-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4- bjindole isomer.
  • the compound with strongest binding affinity for alpha-4-beta-2 nicotinic receptor is 6-fluoro-l-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (38).
  • the compound with strongest binding affinity for sigma-1 receptor is (7S,12bS)- 7,8,9-trifluoro-lH,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (30).
  • the compound with strongest binding affinity for nociceptin / orphanin receptor is (7R,12bR)-7,8,9,10-tetrafluoro-lH,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3- a]quinolizin-4-one (40).
  • the compound with strongest binding affinity for mu-opioid receptor is (7S,12bR)-
  • the compound with strongest binding affinity for delta-opioid receptor is 7,8,9,10- tetrafluoro-lH,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (7), preferably the (7S,12bS)-7,8,9,10-tetrafluoro-lH,2H,3H,4H,6H,7H,12H,12bH- indolo[2,3-a]quinolizin-4-one isomer.

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Abstract

La présente invention concerne des composés de formule générale (I) et des stéréo-isomères et certains de leurs sels pharmaceutiquement acceptables ; R1, R2, R7, Ra, Rb, Rc et le trait en pointillé étant tels que définis dans les revendications. L'invention concerne également des compositions pharmaceutiques comprenant un composé de formule (I) et lesdits composés à des fins d'utilisation en tant que médicament et particulièrement dans le traitement ou dans la prévention de la toxicomanie et de maladies et d'affections associées au SNC. En outre, l'invention concerne des procédés de préparation d'un composé de formule (I), ou d'un de ses stéréo-isomères ou sels pharmaceutiquement acceptables.
PCT/FI2022/050205 2021-03-31 2022-03-30 Nouveaux composés hétérocycliques et leur utilisation WO2022207979A2 (fr)

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IL307377A IL307377A (en) 2021-03-31 2022-03-30 Heterocyclic compounds and their use
EP22715649.4A EP4313985A2 (fr) 2021-03-31 2022-03-30 Nouveaux composés hétérocycliques et leur utilisation
CN202280039184.5A CN117412975A (zh) 2021-03-31 2022-03-30 杂环化合物及其用途
BR112023020273A BR112023020273A2 (pt) 2021-03-31 2022-03-30 Novos compostos heterocíclicos e seus usos
AU2022249834A AU2022249834A1 (en) 2021-03-31 2022-03-30 Heterocyclic compounds and their use
KR1020237037343A KR20240004396A (ko) 2021-03-31 2022-03-30 헤테로사이클릭 화합물 및 그 용도
JP2023561049A JP2024511886A (ja) 2021-03-31 2022-03-30 新規の複素環式化合物およびその使用
CA3215457A CA3215457A1 (fr) 2021-03-31 2022-03-30 Nouveaux composes heterocycliques et leur utilisation

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AU2022249834A1 (en) 2023-11-09
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CA3215457A1 (fr) 2022-10-06
CN117412975A (zh) 2024-01-16
AU2022249834A9 (en) 2023-11-16
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KR20240004396A (ko) 2024-01-11
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